Is Multiple Sclerosis an Autoimmune Disease?

Ben Goldacre is a British physician and journalist. For the last several months his column, Bad Science, has been located above the puzzles on Saturday’s Guardian newspaper, while the regular columnist, the very funny Lucy Mangan, is away on maternity leave. As an obsessive puzzle solver, this has brought me face to face with some of the more ill-informed and disingenuous examples of salesmanship, journalism and political knee-jerkism. Among the things that Ben does is to take widely-accepted mantras, such as video games being bad for your children’s development or the Brain Gym being good for it and subject them to a little scientific rigour. The results are always entertaining and usually reveal how easily we accept mumbo-jumbo as fact. Reading his book, also called Bad Science, has changed the way I view health claims.

Igor, bring me the blood extract of a mutilated goat!

Ben Goldacre’s method is to examine a product, contention or therapy from the perspective of evidence-based science. He trawls through the associated advertising blurb for scientific validity and exposes potty pseudo-science for what it is. After reading Bad Science, you’ll never again be swayed by advertising copy like “Educational Kinesiology”, “Synchronised Recovery Complex” or “Pro-vitamin Enriched”.

There are plenty of theories purporting to explain MS. Some of these represent genuine attempts to understand the disease, some are barmy alternative nonsense and some deceitful attempts to sell snake-oils to vulnerable people. I shall deal with many of these in later blog entries but what I want to address in this article is the idea that multiple sclerosis is an autoimmune disease and apply Ben Goldacre’s technique to that assertion.

I shall try to avoid getting overly technical over the next few paragraphs but, if I lose you, you can always skip to the Conclusion towards the end of this blog.

Autoimmunity is the leading hypothesis trying to explain both the cause and mechanism of MS. The question that is seldom addressed but which is of paramount importance is, “What is the evidence that multiple sclerosis is an autoimmune disease?” Given the amount of research dollars invested and lives risked in dangerous treatments on the assumption of the disease’s autoimmune nature, you might imagine that scientific confidence in that nature is rock-solid. In fact, the reason why this hypothesis has moved from paradigm through dogma to doctrine is rather harder to divine than one might have hoped.

But before we can provide evidence for the autoimmune hypothesis, we’ll have to say what it is:

Though different formulations exist, pretty much all of them finger the villains of the piece to be subpopulations of a particular type of white blood cell, called a T-cell. This type of immune system cell has become programmed to attack proteins in the insulating sheath (the myelin) that coats a portion of some of the nerve cells in the central nervous system. The T-cells cause inflammation, which not only damages the nerves but also breaks down the barrier between the central nervous system and the rest of the body. This in turn allows more components of the immune system to flood in and wreak further havoc. Why some people’s immune systems turn on themselves is generally explained by a genetic propensity acting together with some unknown environmental factor, possibly a virus or traumatic injury [1].

The evidence that multiple sclerosis is an autoimmune disease breaks into two types. The first is that obtained by direct experimental observation – looking at stuff in Petri jars, peering into microscopes and the like. The second type comes from observed similarities to other diseases or by employing some good old-fashioned blue sky thinking. Essentially, this second group, though often persuasive, is what a court of law would call circumstantial evidence. There’s nothing wrong with this type of evidence, it’s just that we should only treat its findings as provisional until they have been placed on firmer footings or are rejected.

There are two main pieces of hard evidence that MS is autoimmune [2]. The first is that another demyelinating disease, acute disseminated encephalomyelitis (ADEM), has myelin damage shown to be associated with immune system cells. The second observation is that mice, which have had brain material injected into them, develop a disease called experimental allergic encephalomyelitis (EAE). In many important ways, EAE is virtually identical to ADEM. Experiments have repeatedly shown both ADEM and EAE to be caused by T-cells attacking proteins in the myelin. [3, 4, 5]

So what is the circumstantial evidence? Well, there’s a quite a lot of it but the better stuff breaks up into six categories:

MRI and tissue samples reveal inflammation around plaques in the brain and spinal cord. [7]

Treatments designed to prevent or reduce inflammation in the central nervous system reduce the number and severity of relapses during the relapsing-remitting phase of the disease.[12, 13 etc.]

Though no one gene has been found to be perfectly linked with multiple sclerosis, several genes do show some degree of correlation and many of these are responsible for coding elements of the immune system.[16]

People with MS have heightened levels of immune system cells that attack myelin proteins.[10, 14]

The profile of people with MS resembles that of other autoimmune diseases such as Rheumatoid Arthritis or Lupus. That is, they tend to be young at disease onset and are more likely to be female. [17]

Many important neurologists believe that MS is autoimmune and several pharmaceutical companies derive significant revenue streams based on the disease’s autoimmune nature.

All this seems like a substantial volume of data all pointing in the same direction, doesn’t it? Well, let’s look at it a bit harder before jumping to any conclusions.

The obvious disconnect with both pieces of experimental data is that while ADEM and MS can be sometimes confused in a clinical setting, ADEM is not MS. It is an acute disease that strikes once whereas multiple sclerosis is a chronic condition that erupts repeatedly, sometimes without letting up [6]. The lesions in ADEM are very different to those in MS. In fact, in one third of multiple sclerosis lesions, T-cells are entirely absent [2, 8].

This leads us nicely into our first category of circumstantial evidence: that inflammation is present in MS lesions. Well, as just shown in the last paragraph, it’s not. At least, not always. In progressive forms of the disease, it can be entirely absent as demonstrated by a type of computerised brain scan called Diffusion Tensor MRI [18], by the early alemtuzumab trials [19] and by the fact that no immune modifying treatment has any effect on progressive forms of the disease where relapses are absent.

More damning still, is a study by Barnett and Prineas published in 2004 [9, 20]. The researchers examined brain material from 12 patients with relapsing-remitting multiple sclerosis, including a poor 14-year old girl, who had died from an MS lesion affecting her vagus nerve. From this they were able to draw up a natural history of the developing multiple sclerosis lesion. The first sign of damage was wide-scale death of the myelin-producing cells, the oligodendrocytes. This was in the absence of any immune system cells. The first immune system cells to appear were not the T-cells but another type of immune system cell altogether, the macrophages. This paper is acutely embarrassing to adherents of the autoimmune school.

So if MS is not autoimmune, why do immune-modifying therapies work? Well, no one is saying that inflammation is not a feature of the multiple sclerosis lesion – clearly it is. The point is more whether the target of immune system attack is the body’s own proteins or something else, perhaps a virus or bacteria. One might expect an immune response to a foreign invader and it may be that the resulting inflammation causes some temporary or permanent damage. What is clear is that inflammatory lesions are by no means the whole picture and that, in progressive forms of the disease, the considerable disability incurred happens through another mechanism.

And then there are all these immune system genes weakly correlated to multiple sclerosis. This shouts “an immunological disease at the beginning” said one researcher [15]. Perhaps, but it could also indicate a genetic vulnerability to a particular virus or bacteria. Wouldn’t that be the most likely result of immune system mutations? A compromised immune system? That would be my expectation.

But if MS is not autoimmune, why do people with multiple sclerosis have T-cell populations that target myelin proteins? The answer to this question is not clear. All that can be said is that people who don’t have MS also have these T-cell populations, albeit at lower levels, so it seems to be a function of having an immune system rather than of having MS [21]. But the levels are raised in people with MS, so perhaps there is an element of immune system dysregulation after all. This is what some people think anyway [22] or even some level of apparent autoimmunity caused by a virus [23].

Conclusion

Men will die upon dogma but will not fall victim to a conclusion.
John Henry Newman

“Aha!” you say, “but why is autoimmunity the prevailing paradigm of both the medical profession and the pharmaceutical industry. Are you saying that, you, a nobody, knows better than all these important, learned and clever people?”

No, I’m not so arrogant as to think I know better than the experts. It’s just that the experts themselves are divided and plenty of them question whether MS is autoimmune. I’ve just looked at the arguments on both sides and presented the work in a way that seems logical to me.

I think the reason that the autoimmune theory has become doctrine might not be because of its superiority to the alternatives but more to do with how much is invested in it. It’s not just the careers of a good many eminent neurologists and research fellows but also many millions of dollars in disease-modifying treatments by the pharmaceutical industry. For comparison, look at the vitriol poured on Barry Marshall by his peers and the pharmaceutical industry when he suggested that stomach ulcers were caused by helicobacter pylori[11]. His work is now canonical.

A journalist in this Saturday’s Guardian was joking that Albert Einstein was lucky he didn’t have to apply for a research grant because he would have been unsuccessful. Anyone looking to break the mould is not going to find much support in a jury of his/her peers and that is what you need to get a peer reviewed grant.

So what do we, as people with MS, do. We could go on taking part in treatments based on the autoimmune theory – some of which, for example Hemapoietic Stem Cell Replacement and mitoxantrone, are potentially extremely dangerous – or we can ask our representatives, the MS Societies of the world, not to invest so much of their research budgets into a potentially failed Autoimmune paradigm until its veracity is firmly established.

We need them to look for the cause of multiple sclerosis as a priority.

A quick scan of the current research projects funded by the British MS Society shows that very little money is going in this direction. They have 25 projects listed under “Cause” but almost all of these aren’t looking for a cause at all or are based on the supposition that MS is autoimmune. I really don’t understand how “Finding a way to make oligodendrocytes” or “Understanding the biological mechanisms of spasticity” are to do with a cause at all. I feel another blog coming on.

Please write to your MS Society and ask them to put more effort into really looking for the cause. I did. I got no response.

Coming soon. Is Epstein-Barr virus linked to Multiple Sclerosis?

References

I’ve moved the references to this page so that people can read straight on through to the responses or the next blog. (You can click the superscript reference numbers in the blog to go straight to the appropriate place on the reference page.)

5 comments on “Is Multiple Sclerosis an Autoimmune Disease?”

I’m going to highlight a couple of things from my Autologous Hemapoietic Stem Cell Transplant (AHSCT), but they probably don’t shed any more light on the autoimmune or not debate. Still, it will be a look inside a treatment which works.

AHSCT was thought to be a way to cut-off the autoimmune attacks at the source (bone marrow is the source of T-cells, a type of white blood cell). The idea was to take some of my stem cells from my marrow, clean them of any other blood cells, i.e., set aside a collection of stem cells in plasma, then kill my bone marrow so that I was no longer producing white blood cells. Then, they monitored my blood and waited for my white blood cell count to go to zero. At that point, I no longer had an adaptive immune system (and, that is why this procedure is dangerous). Then, I got my clean stem cells reinfused so that I could develop a new immune system which ideally would no longer attack myelin. A good plan to attack an autoimmune disease.

But, it didn’t work. After my new immune system developed, tests of my blood showed that I still had T-cells that were reactive to myelin. So, maybe MS isn’t an autoimmune disease.

But, it did work. Seven of us went through the trial at Methodist Hospital in Houston. After treatment, six no longer had exacerbations. (The seventh was the only primary progressive in the trial.) I haven’t had an exacerbation in nearly ten years. So, maybe MS is an autoimmune disease, but T-cells are the wrong target.

I read the paper published on the Houston results. Interleukin-12 (IL-12), an immune system signaling agent went to zero in all the patients. I pointed this out to the lead researcher, but for some reason, he was not comfortable with drawing what I thought was an obvious conclusion. Some time later, I read that Abbott Labs was trialing an anti-IL-12 monoclonal antibody. I haven’t kept track of how that went.

From my experience, MS may or may not be an autoimmune disease, but it can be halted by tinkering with the immune system.

I’m a fitness intructor and the fitness world is clueless on how to properly train people with MS. My friend Roxana has MS and she was currently taking Copaxone, Excuse my spelling. Her doctor put her on Mitoxantrone. I heard its dangerous, however, I’m taking it upon myself to put more research of proper excersises for clients with MS. If anyone has any questions Feel free to ask.

People with MS are not ‘people’ to the pharmaceutical industry – we are ‘the MS market’. As it says in the report above “identify, understand, capitalise”.

According to Tan et al
With MR venography, the perivenous distribution of MS lesions in the brain can be visualized in vivo. The venous anatomy defines the typical form and orientation of these lesions”.

there is no chance of the MS Society replying to your reasonable enquiry because they are ground troops for the pharmaceutical industry.
see pages 74 and 76